Processes for the preparation of dipyridamole

ABSTRACT

The present invention relates to the active pharmaceutical ingredient dipyridamole. In particular, it relates to efficient processes for the preparation of dipyridamole which are amenable to large scale commercial production and provide the required product with improved yield and purity. The present invention also relates to a novel crystallization method for the purification of dipyridamole.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 13/700,845, filed Feb.25, 2013, which is a 371 National Stage Application of InternationalApplication No. PCT/GB2011/051023, filed May 31, 2011, which claimsforeign priority to India Patent Application No. 1655/MUM/2010, filedMay 31, 2010, the contents of which are incorporated herein in theirentirety for all purposes.

FIELD OF THE INVENTION

The present invention relates to the active pharmaceutical ingredientdipyridamole. In particular, it relates to efficient processes for thepreparation of dipyridamole which are amenable to large scale commercialproduction and provide the required product with improved yield andpurity. The present invention also relates to a novel crystallizationmethod for the purification of dipyridamole.

BACKGROUND OF THE INVENTION

Dipyridamole, represented by structural formula (I), possesses plateletaggregation inhibiting, anti-thrombotic and vasodilator properties andit is marketed as an anti-platelet therapy for the treatment andprevention of disorders such as thrombo-embolisms.

A process for the preparation of dipyridamole, disclosed in U.S. Pat.No. 3,031,450, involves the reaction of2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine withdiethanolamine (see Scheme 1). The preparation of2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine is also reportedin U.S. Pat. No. 3,031,450 and is incorporated herein by reference. Thereaction to prepare dipyridamole does not employ an additional reactionsolvent and is a neat mixture of the two reactants carried out at a veryhigh temperature of 190 to 195° C. The process also involves acumbersome work-up to isolate dipyridamole, since the crude productobtained is a pasty mass which needs decantation of the mother liquorand further purification. This decantation process is not practical oncommercial scale.

A similar process for the production of dipyridamole is described inpatent DD 117456 wherein the reaction conditions exemplified are heating2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine anddiethanolamine at 155 to 160° C. under vacuum. However, this processagain requires a high temperature which leads to the formation ofimpurities.

A process for the preparation and purification of dipyridamole isdisclosed in patent DE 1812918, wherein2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine anddiethanolamine are heated to 150 to 200° C. After completion of thereaction, the reaction mixture is dissolved in chloroform, which isfurther separated into an upper layer of diethanolamine and itshydrochloride and a chloroform solution. The chloroform solutionobtained is separated and reduced to dryness after stirring with water.This process also requires a high temperature which can lead to theformation of impurities. In addition, the solvent used for the isolationof dipyridamole, chloroform, is inconvenient as it is a restrictedsolvent and its permitted limit in the final marketed dipyridamole isvery low.

A similar process, wherein dipyridamole is manufactured by the reactionof diethanolamine with2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine is disclosed inpatent RO 104718. However, this process again requires high temperaturesof 180 to 200° C. which leads to the formation of impurities and,consequently, the yield of the final product is very low (58%) with apurity of less than 98%.

A process is disclosed in patent DD 115670, wherein the purification ofdipyridamole involves refluxing it in butyl acetate, AcOBu, for 2 hoursin the presence of an equal amount of silica gel or columnchromatography on silica gel at 60-100° C. However, purification bycolumn chromatography is not economical and not feasible on industrialscale. Moreover, this purification process only removes one specificimpurity, 2,4,6-tris-(diethanolamino)-8-piperidino-pyrimido(5,4-d)pyrimidine.

The processes described above to prepare dipyridamole do not employ anadditional reaction solvent but involve neat mixtures of the tworeactants, 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine anddiethanolamine, which are heated at very high temperatures. The use ofneat reaction mixtures and/or high temperatures means that it is verydifficult to control the levels of impurities formed.

Another process for the preparation of dipyridamole, disclosed in patentapplication WO 2007/080463, involves reacting diethanolamine with2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine in a solventselected from the group consisting of 1-methyl-2-pyrrolidinone,sulpholane and polyethylene glycol. However, the exemplified reactiontemperatures are very high at 190 to 200° C. and the HPLC purity of thecrude dipyridamole is reported to be only 90-94%. A purification methodis disclosed using first a ketonic solvent and then an alcohol andwater. Even though the process disclosed in this patent application usesa solvent in the reaction, the temperature of reaction is still veryhigh and the purification in ketonic solvent is reported at hightemperature (100 to 120° C.). The HPLC purity after purification isreported as only 99.0-99.5%.

As discussed above, all the processes disclosed in the prior art for thepreparation of dipyridamole suffer from serious disadvantages withrespect to commercial production. The prior art synthetic andpurification processes employ high temperatures in the preparation ofdipyridamole which leads to inefficiency and high processing costs. Thehigh temperatures also lead to higher levels of impurities being formedduring manufacture with the consequence that further cumbersome andexpensive purification procedures are required.

Considering the importance gained by dipyridamole as a commercialmedicine, there is a great need for developing simple, inexpensive, goodyielding and commercially feasible processes for the manufacture of highquality dipyridamole.

OBJECT OF THE INVENTION

Therefore there is a need for improved processes for the synthesis andpurification of dipyridamole which provide commercial quantities ofdipyridamole conveniently, economically and with high yield and purity.A further objective is to provide extremely pure dipyridamolesubstantially free of all impurities.

SUMMARY OF THE INVENTION

The term ‘dipyridamole’ as used herein throughout the description andclaims means dipyridamole and/or any salt, solvate or isomer thereofunless specified otherwise.

A first aspect of the present invention provides a process for thepreparation of dipyridamole comprising reacting2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine withdiethanolamine at a temperature below 130° C., preferably below 125° C.Preferably the reaction temperature is between about 100° C. and below130° C., preferably between about 100° C. and about 125° C., preferablybetween about 110° C. and about 125° C., preferably between about 110°C. and about 120° C., preferably between about 110° C. and about 115°C., and most preferably between about 113° C. and about 115° C.

Preferably, in a process according to the first aspect of the presentinvention, the reaction mixture is a neat mixture of the two reactants,2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine anddiethanolamine, with no additional reaction solvent. Preferably the2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine is dissolved inthe diethanolamine.

Alternatively, in a process according to the first aspect of the presentinvention, an additional reaction solvent may be used. Preferably theadditional reaction solvent is a polar aprotic solvent, preferablydimethylsulfoxide (DMSO). Alternatively other solvents can be used.Preferred alternative solvents are other polar aprotic solvents, such asdimethylformamide (DMF), dimethylacetamide (DMA) orN-methyl-2-pyrrolidinone (NMP). Alternatively, hydrocarbon solvents canbe used. Preferred hydrocarbon solvents are aromatic hydrocarbonsolvents such as toluene or xylene.

Optionally, the intermediate compound,2-chloro-6-diethanolamino-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine, isisolated before being reacted with diethanolamine to form dipyridamole.

Irrespective of whether the reaction mixture is a neat mixture of thetwo reactants or an additional reaction solvent is used, preferablysolvents are used during the work-up of the reaction. Preferred solventsused for the work-up are ethanol, toluene and water. Alternatively othersolvents can be used. Preferred alternative solvents are other C₁-C₆alkyl alcohols instead of ethanol and other hydrocarbon solvents insteadof toluene, particularly aromatic hydrocarbon solvents such as xylene.

A particularly preferred process for the preparation of dipyridamoleaccording to the present invention comprises the steps of:

-   (a) providing a mixture of    2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine and    diethanolamine;-   (b) heating the mixture from step (a);-   (c) adding a C₁-C₆ alkyl alcohol to the solution from step (b);-   (d) adding a hydrocarbon solvent to the solution from step (c);-   (e) adding water to the solution from step (d);-   (f) cooling the mixture from step (e); and-   (g) isolating the resulting solid.

Preferably this preferred process comprises the steps of:

-   (a) providing a mixture of    2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine and    diethanolamine;-   (b) heating the mixture from step (a);-   (c) adding ethanol to the solution from step (b);-   (d) adding toluene to the solution from step (c);-   (e) adding water to the solution from step (d);-   (f) cooling the mixture from step (e); and-   (g) isolating the resulting solid.

Preferably these preferred processes are carried out at a temperaturebelow 130° C., preferably below 125° C.

Another particularly preferred process for the preparation ofdipyridamole according to the present invention comprises the steps of:

-   (a) providing a mixture of    2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine,    diethanolamine and either a polar aprotic solvent or a hydrocarbon    solvent;-   (b) heating the mixture from step (a);-   (c) adding a C₃-C₈ alkyl ketone or C₃-C₈ alkyl nitrile solvent to    the solution from step (b);-   (d) adding water to the solution from step (c);-   (e) cooling the mixture from step (d);-   (f) isolating the resulting    2-chloro-6-diethanolamino-4,8-dipiperidino-pyrimido(5,4-d)    pyrimidine;-   (g) preferably drying the solid;-   (h) providing a mixture of    2-chloro-6-diethanolamino-4,8-dipiperidino-pyrimido(5,4-d)    pyrimidine and diethanolamine;-   (i) heating the mixture from step (h);-   (j) adding a C₁-C₆ alkyl alcohol to the solution from step (i);-   (k) adding a hydrocarbon solvent to the solution from step (j);-   (l) adding water to the solution from step (k);-   (m) cooling the mixture from step (l); and-   (n) isolating the resulting solid.

Preferably this preferred process comprises the steps of:

-   (a) providing a mixture of    2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine,    diethanolamine and dimethylsulfoxide;-   (b) heating the mixture from step (a);-   (c) adding acetone to the solution from step (b);-   (d) adding water to the solution from step (c);-   (e) cooling the mixture from step (d);-   (f) isolating the resulting    2-chloro-6-diethanolamino-4,8-dipiperidino-pyrimido(5,4-d)    pyrimidine;-   (g) drying the solid;-   (h) providing a mixture of    2-chloro-6-diethanolamino-4,8-dipiperidinopyrimido(5,4-d) pyrimidine    and diethanolamine;-   (i) heating the mixture from step (h);-   (j) adding ethanol to the solution from step (i);-   (k) adding toluene to the solution from step (j);-   (l) adding water to the solution from step (k);-   (m) cooling the mixture from step (l); and-   (n) isolating the resulting solid.

Preferably these preferred processes are carried out at a temperaturebelow 130° C., preferably below 125° C.

Preferably any process according to the first aspect of the presentinvention provides dipyridamole in a molar yield of more than 60%,preferably more than 65%, preferably more than 70%, preferably more than75%, preferably more than 80%, preferably more than 85%, from2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine.

Preferably any process according to the first aspect of the presentinvention provides dipyridamole on an industrial scale, preferably inbatches of 100 g or more, 250 g or more, 500 g or more, 1 kg or more, 5kg or more, 10 kg or more, 20 kg or more, or 50 kg or more.

Preferably any process according to the first aspect of the presentinvention is carried out without the use of any chromatographypurification techniques.

A second aspect according to the present invention provides a processfor the purification of dipyridamole comprising the steps of:

(a) heating a mixture of crude dipyridamole and diethanolamine to get aclear solution;(b) adding a C₁-C₆ alkyl alcohol to the solution from step (a);(c) adding a hydrocarbon solvent to the solution from step (b);(d) adding water to the solution from step (c);(e) cooling the mixture from step (d); and(f) isolating the resulting solid.

Preferably the process according to the second aspect of the presentinvention comprises the steps of:

(a) heating a mixture of crude dipyridamole and diethanolamine to get aclear solution;(b) adding ethanol to the solution from step (a);(c) adding toluene to the solution from step (b);(d) adding water to the solution from step (c);(e) cooling the mixture from step (d); and(f) isolating the resulting solid.

Preferably the process according to the second aspect of the presentinvention is carried out at a temperature below 90° C.

Preferably any process according to the second aspect of the presentinvention provides purified dipyridamole in a molar yield of more than70%, preferably more than 80%, preferably more than 85%, preferably morethan 90%, preferably more than 95%, from crude dipyridamole.

Preferably any process according to the second aspect of the presentinvention provides purified dipyridamole on an industrial scale,preferably in batches of 100 g or more, 250 g or more, 500 g or more, 1kg or more, 5 kg or more, 10 kg or more, 20 kg or more, or 50 kg ormore.

Preferably any process according to the second aspect of the presentinvention is carried out without the use of any chromatographypurification techniques.

A third aspect according to the present invention provides dipyridamoleprepared by a process according to the first or second aspect of thepresent invention. Preferably the dipyridamole according to the thirdaspect has a chemical purity of more than 99%, preferably more than99.5%, more preferably more than 99.8%, and most preferably more than99.9% (as measured by HPLC). Preferably the dipyridamole according tothe third aspect comprises less than 0.1% of one or more of impurities Ato F, preferably less than 0.05% of one or more of impurities A to F (asmeasured by HPLC) (see FIG. 1 for the structures of impurities A to F).Preferably the dipyridamole according to the third aspect comprises lessthan 0.1% of one or more of impurities A to G, preferably less than0.05% of one or more of impurities A to G (as measured by HPLC) (seeFIG. 1 for the structures of impurities A to G).

A fourth aspect according to the present invention provides dipyridamolewith a chemical purity of greater than 99%, preferably greater than99.5%, more preferably greater than 99.8%, and most preferably greaterthan 99.9% (as measured by HPLC). Preferably the dipyridamole accordingto the fourth aspect comprises less than 0.1% of one or more ofimpurities A to F, preferably less than 0.05% of one or more ofimpurities A to F (as measured by HPLC) (see FIG. 1 for the structuresof impurities A to F). Preferably the dipyridamole according to thefourth aspect comprises less than 0.1% of one or more of impurities A toG, preferably less than 0.05% of one or more of impurities A to G (asmeasured by HPLC) (see FIG. 1 for the structures of impurities A to G).

A fifth aspect according to the present invention provides dipyridamolecomprising less than about 0.1% of one or more of impurities A to F,preferably comprising less than about 0.05% of one or more of impuritiesA to F (as measured by HPLC) (see FIG. 1 for the structures ofimpurities A to F). The fifth aspect according to the present inventionalso provides dipyridamole comprising less than about 0.1% of one ormore of impurities A to G, preferably comprising less than about 0.05%of one or more of impurities A to G (as measured by HPLC) (see FIG. 1for the structures of impurities A to G). Preferably the dipyridamoleaccording to the fifth aspect has a chemical purity of more than 99%,preferably more than 99.5%, more preferably more than 99.8%, and mostpreferably more than 99.9% (as measured by HPLC).

Preferably the dipyridamole according to the third, fourth and fifthaspects of the present invention is suitable for use in medicine,preferably for treating or preventing platelet aggregation and forpreventing thrombosis, ischaemic stroke and transient ischaemic attacks.

A sixth aspect according to the present invention provides apharmaceutical composition comprising dipyridamole according to thethird, fourth or fifth aspect of the present invention. Preferably thepharmaceutical composition according to the sixth aspect comprises oneor more pharmaceutically acceptable excipients. Optionally, thepharmaceutical composition according to the sixth aspect furthercomprises aspirin.

A seventh aspect according to the present invention provides the use ofdipyridamole according to the third, fourth or fifth aspect of thepresent invention in the preparation of a medicament for treating orpreventing platelet aggregation or for preventing thrombosis, ischaemicstroke or transient ischaemic attacks. Optionally, the medicamentcomprises dipyridamole and aspirin.

An eighth aspect according to the present invention provides a methodfor treating or preventing platelet aggregation or for preventingthrombosis, ischaemic stroke or transient ischaemic attacks, the methodcomprising administering to a patient in need thereof a therapeuticallyor prophylactically effective amount of dipyridamole according to thethird, fourth or fifth aspect of the present invention or atherapeutically or prophylactically effective amount of thepharmaceutical composition according to the sixth aspect of the presentinvention. Preferably the patient is a mammal, preferably a human.Optionally, the method according to the eighth aspect comprisesadministering to a patient in need thereof a therapeutically orprophylactically effective amount of aspirin in addition to thetherapeutically or prophylactically effective amount of dipyridamole.

BRIEF DESCRIPTION OF THE ACCOMPANYING FIGURES

FIG. 1 shows the structures of impurities A to G.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides improved processes for the preparation ofdipyridamole, particularly for the preparation of highly puredipyridamole. The improved processes are simple, inexpensive, goodyielding and can be easily adopted for commercial production with a highdegree of consistency and reproducibility.

The present inventors have surprisingly discovered that the use of lowerreaction temperatures for the reaction of diethanolamine with2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine to formdipyridamole still affords complete reaction in a convenient time scale,but markedly reduces the levels of impurities formed in the reaction.The use of the lower reaction temperatures in the process according tothe invention significantly controls the formation of impurities. Crudedipyridamole having a purity of greater than 98% was obtained by thisprocess.

The present inventors have also developed a low temperature process ofconverting 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine tothe mono-substituted product,2-chloro-6-diethanolamino-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine, bytreating 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine withdiethanolamine in a solvent. The mono-substituted intermediate is thenconverted to dipyridamole by reacting it with diethanolamine at lowtemperature. The isolation of2-chloro-6-diethanolamino-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine andfurther conversion to dipyridamole at lower temperature, in a processaccording to the invention, controls the formation of significant levelsof impurities. Crude dipyridamole having a purity of greater than 98%was obtained by this process.

The levels of impurities in the crude product obtained in the processesof the present invention are significantly lower than in prior artprocesses. As a consequence, work-up and purification procedures becomefar more convenient than those disclosed in the prior art anddipyridamole with very high purity is easily and conveniently obtained.

A low temperature purification method to obtain dipyridamole with morethan 99.8% purity has also been developed. The purification is achievedby using a novel solvent system, preferably comprising diethanolamine,ethanol, toluene and water. The reaction conditions and furtherpurification method control the formation of all known and unknownimpurities to well below acceptable levels, but employ temperatures muchlower than prior art crystallization procedures.

In the processes according to the present invention2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine is added todiethanolamine. In preferred embodiments the mixture is heated tosubstantially dissolve the2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine. Preferably thistemperature is about 110-125° C., most preferably about 113-115° C.

Therefore the processes of the present invention comprise improved anddefined process parameters for the manufacturing of dipyridamole whereinthe formation of impurities is precisely controlled and minimized. Inaddition, the processes of the present invention offer simpler work-upand/or purification procedures with optimum conditions for improvedyield and quality with minimum contamination with process impurities.The improved processes can be easily adapted on commercial scale asefficient and convenient processes.

Advantageously, the processes of the present invention avoid columnchromatography purification techniques, thereby making the processessimpler and more adaptable for large scale commercial production.

Further aspects of the present invention provide dipyridamole of greaterthan 99% purity (as measured by HPLC). Preferably the dipyridamole ofthe present invention has a purity of greater than 99.5%, morepreferably greater than 99.8%, and most preferably greater than 99.9%.

The high quality dipyridamole prepared by the processes according to thepresent invention can be used for the preparation of a pharmaceuticalcomposition to use in the manufacture of a medicament for anti-platelettherapy.

A preferred embodiment of the present invention, illustrated in Scheme2, provides a process for the preparation of dipyridamole comprisingreacting 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine withdiethanolamine at 113-115° C. This reaction temperature is significantlylower than that used in the prior art processes to prepare dipyridamole.

Another preferred embodiment of the present invention, illustrated inScheme 3, also provides a process for the preparation of dipyridamole bythe reaction of 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidinewith diethanolamine in dimethylsulfoxide at 120-125° C. to afford themono-substituted intermediate,2-chloro-6-diethanolamino-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine,which is isolated and then further converted to dipyridamole by heatingin diethanolamine at 113-115° C.

Although the solvent used in this preferred embodiment of the presentinvention is preferably dimethylsulfoxide (DMSO), other solvents canalternatively be used. Preferred alternative solvents are other polaraprotic solvents, such as dimethylformamide (DMF), dimethylacetamide(DMA) or N-methyl-2-pyrrolidinone (NMP). Alternatively, hydrocarbonsolvents can be used. Preferred hydrocarbon solvents are aromatichydrocarbon solvents such as toluene or xylene.

The crude dipyridamole obtained in preferred embodiments of the presentinvention or by any other processes, is preferably purified by using anovel solvent system consisting of diethanolamine, ethanol, toluene andwater in a single step to afford highly pure dipyridamole.

In preferred embodiments of the present invention, pure dipyridamole isobtained substantially free of one or more of impurities A to G. Thestructures of impurities A to G are illustrated in FIG. 1.

A particularly preferred embodiment of the first aspect of the presentinvention comprises the following steps:

-   (a) providing a mixture of    2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine and    diethanolamine;-   (b) heating the mixture from step (a);-   (c) adding ethanol to the solution from step (b);-   (d) adding toluene to the solution from step (c);-   (e) adding water to the solution from step (d);-   (f) cooling the mixture from step (e); and-   (g) isolating the resulting solid.

Preferably the mixture from step (a) is heated to between about 110 to125° C., preferably the mixture is heated to between about 113 to 115°C. Preferably ethanol is added to the mixture from step (b) at about60-80° C., more preferably at about 75-80° C. Preferably toluene isadded to the mixture from step (c) at about 60-80° C., more preferablyat about 70-75° C. Preferably water is added to the mixture from step(d) at about 50-70° C., more preferably at about 60-65° C. Preferablythe mixture from step (e) is cooled at about 20-40° C., more preferablyat about 25° C. Preferably the solid from step (f) is isolated byfiltration and preferably the solid is further washed, most preferablywith water. Preferably the solid is further dried, preferably undervacuum. Although the two organic solvents used in this aspect of thepresent invention are preferably ethanol and toluene, other solvents canalternatively be used. Preferred alternative solvents are other C₁-C₆alkyl alcohols instead of ethanol and other hydrocarbon solvents insteadof toluene, particularly aromatic hydrocarbon solvents such as xylene.

Another preferred embodiment of the first aspect of the presentinvention comprises the following steps:

-   (a) providing a mixture of    2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine,    diethanolamine and dimethylsulfoxide;-   (b) heating the mixture from step (a);-   (c) adding acetone to the solution from step (b);-   (d) adding water to the solution from step (c);-   (e) cooling the mixture from step (d);-   (f) isolating the resulting solid    2-chloro-6-diethanolamino-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine;-   (g) drying the solid;-   (h) providing a mixture of    2-chloro-6-diethanolamino-4,8-dipiperidino-pyrimido(5,4-d)    pyrimidine and diethanolamine;-   (i) heating the mixture from step (h);-   (j) adding ethanol to the solution from step (i);-   (k) adding toluene to the solution from step (j);-   (l) adding water to the solution from step (k);-   (m) cooling the mixture from step (l); and-   (n) isolating the resulting solid.

Preferably the mixture from step (a) is heated to between about 110 and130° C., more preferably the mixture is heated to about 120-125° C.Preferably acetone is added to the mixture from step (b) at about 45-60°C., more preferably at about 55-60° C. Preferably water is added to themixture from step (c) at about 50-70° C., more preferably at about55-60° C. Preferably the mixture from step (d) is cooled at about 20-40°C., more preferably at about 25° C. Preferably the resultant solid fromstep (e) is isolated in step (f) by filtration and preferably the solidis further washed, most preferably with water. Preferably the solid isfurther dried, preferably under vacuum. Preferably the mixture from step(h) is heated to between about 110 and 125° C., more preferably themixture is heated to about 113-115° C. Preferably ethanol is added tothe mixture from step (i) at about 60-80° C., more preferably at about75-80° C. Preferably toluene is added to the mixture from step (j) atabout 60-80° C., more preferably at about 70-75° C. Preferably water isadded to the mixture from step (k) at about 50-70° C., more preferablyat about 60-65° C. Preferably the mixture from step (l) is cooled atabout 20-40° C., more preferably at about 25° C. Preferably theresultant solid from step (m) is isolated by filtration and preferablythe solid is further washed, most preferably with water. Preferably thesolid is further dried, preferably under vacuum. Although the fourorganic solvents used in this aspect of the present invention arepreferably DMSO, acetone, ethanol and toluene, other solvents canalternatively be used. Preferred alternative solvents are: instead ofDMSO other polar aprotic solvents such as dimethylformamide (DMF),dimethylacetamide (DMA) or N-methyl-2-pyrrolidinone (NMP) or hydrocarbonsolvents such as aromatic hydrocarbon solvents such as toluene orxylene; instead of acetone other C₃-C₈ alkyl ketones or alkyl nitrilessuch as acetonitrile; instead of ethanol other C₁-C₆ alkyl alcohols; andinstead of toluene other hydrocarbon solvents, particularly aromatichydrocarbon solvents such as xylene.

A preferred embodiment of the second aspect of the present inventioncomprises the following steps:

-   (a) heating a mixture of crude dipyridamole and diethanolamine to    obtain a clear solution;-   (b) adding ethanol to the solution from step (a);-   (c) adding toluene to the solution from step (b);-   (d) adding water to the solution from step (c);-   (e) cooling the mixture from step (d); and-   (f) isolating the resulting solid.

Preferably the mixture from step (a) is heated to between about 60 and90° C., more preferably the mixture is heated to about 75-80° C.Preferably ethanol is added to the mixture from step (a) at about 60-80°C., preferably at about 75-80° C. Preferably toluene is added to themixture from step (b) at about 60-80° C., more preferably at about70-75° C. Preferably water is added to the mixture from step (c) atabout 50-75° C., more preferably at about 70-75° C. Preferably themixture from step (d) is cooled at about 20-40° C., more preferably atabout 25° C. Preferably the resultant solid from step (e) is isolated byfiltration and preferably the solid is further washed, most preferablywith water. Preferably the solid is further dried, preferably undervacuum. Although the two organic solvents used in this aspect of thepresent invention are preferably ethanol and toluene, other solvents canalternatively be used. Preferred alternative solvents are other C₁-C₆alkyl alcohols instead of ethanol and other hydrocarbon solvents insteadof toluene, particularly aromatic hydrocarbon solvents such as xylene.

A further aspect of the present invention provides dipyridamolecomprising less than about 0.1%, preferably less than about 0.05% ofimpurities A to G and/or any other unknown impurities.

The dipyridamole prepared by the improved processes according to thepresent invention is >99.8% pure by HPLC analysis and morepreferably >99.9% pure by HPLC analysis.

The dipyridamole prepared by the improved processes according to thepresent invention can be easily converted into any suitable salt ifrequired. The highly pure dipyridamole can be converted into a salt, ifrequired, with a chemical purity >99.9% (as measured by HPLC). Typicalsalts are preferably pharmaceutically acceptable addition salts withsuitable acids, including but not limited to inorganic acids such ashydrohalogenic acids (for example, hydrofluoric, hydrochloric,hydrobromic or hydroiodic acid) or other inorganic acids (for example,nitric, perchloric, sulphuric or phosphoric acid); or organic acids suchas organic carboxylic acids (for example, propionic, butyric, glycolic,lactic, mandelic, citric, acetic, benzoic, salicylic, succinic, malic orhydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, mucic orgalactaric, gluconic, pantothenic or pamoic acid), organic sulphonicacids (for example, methanesulphonic, trifluoromethanesulphonic,ethanesulphonic, 2-hydroxyethanesulphonic, benzenesulphonic,toluene-p-sulphonic, naphthalene-2-sulphonic or camphorsulphonic acid)or amino acids (for example, ornithinic, glutamic or aspartic acid). Theacid addition salt may be a mono-, di- or tri-acid addition salt.

Further details of the invention are illustrated below in the followingnon-limiting examples.

EXAMPLES

As used hereinafter in the examples, the term ‘1 vol’ means that foreach gram of starting material 1 ml of solvent is used. The terms ‘2vol’, ‘3 vol’ etc. are used accordingly.

Example 1 Preparation of Crude Dipyridamole

Diethanolamine (10 vol) and2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine (1 eq) weremixed at 25-30° C., stirred for 10 minutes and then heated at 113-115°C. for 45-48 hours. After completion of the reaction, the mixture wascooled to 75-80° C. Ethanol (5 vol) was added at 75-80° C. and themixture was stirred at 75-80° C. for 10 minutes. Toluene (10 vol) wasadded at 70-75° C. and the mixture was stirred at 70-75° C. for 15minutes. Purified water (15 vol) was added at 70-75° C. and the mixturewas stirred at 60-65° C. for 30 minutes. The mixture was then cooled andstirred at 25-30° C. for 30 minutes. The precipitated solid was filteredand washed with purified water (2×5 vol) before drying at 75-80° C.under reduced pressure afforded crude dipyridamole as a yellowcrystalline solid.

Yield (w/w)=80-85%Yield (molar)=58-62%HPLC purity ≧98%

Example 2 Stage 1: Preparation of2-chloro-6-diethanolamino-4,8-dipiperidino-pyrimido(5,4-d) pyrimidine

Diethanolamine (3 eq) and2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine (1 eq) wereadded to dimethylsulfoxide (10 vol) at 25-30° C., stirred for 10 minutesand then heated at 120-125° C. for 4-5 hours. After completion of thereaction, the reaction mixture was cooled to 55-60° C. Acetone (5 vol)was added at 55-60° C. and the mixture was stirred at 55-60° C. for 10minutes. Purified water (15 vol) was added at 55-60° C. and the mixturewas stirred at 50-55° C. for 15 minutes. The mixture was cooled to25-30° C. and stirred at 25-30° C. for 30 minutes. The precipitatedsolid was filtered, washed with purified water (2×5 vol) and dried at75-80° C. under reduced pressure to afford crude2-chloro-6-diethanolamino-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine asa yellow crystalline solid.

Yield (w/w)=110-120%Yield (molar)=93-100%HPLC purity ≧96%

Stage 2: Preparation of crude dipyridamole

Diethanolamine (10 vol) and2-chloro-6-diethanolamino-4,8-dipiperidino-pyrimido(5,4-d) pyrimidine (1eq) were mixed at 25-30° C., stirred for 10 minutes and then heated at113-115° C. for 45-48 hours. After completion of the reaction, themixture was cooled to 75-80° C. Ethanol (5 vol) was added and themixture was stirred at 75-80° C. for 10 minutes. Toluene (10 vol) wasadded and the mixture was stirred at 70-75° C. for 15 minutes. Purifiedwater (15 vol) was added and the mixture was stirred at 60-65° C. for 30minutes. The mixture was then cooled to 25-30° C. and stirred for 30minutes. The precipitated solid was filtered, washed with purified water(2×5 vol) and dried at 75-80° C. under reduced pressure to afford crudedipyridamole as a yellow crystalline solid.

Yield (w/w)=95-97%Yield (molar)=82-84%HPLC purity ≧98%

Example 3 Crystallization of Crude Dipyridamole

Crude dipyridamole (1 eq) and diethanolamine (8 vol) were stirredtogether at 25-30° C. for 10 minutes and then heated to about 80° C. for10 minutes. The clear solution was cooled to 75-80° C., ethanol (5 vol)was added and the mixture was stirred at 75-80° C. for 10 minutes.Toluene (10 vol) was added and the mixture was stirred at 70-75° C. for15 minutes. The mixture was cooled to 25-30° C., stirred at 25-30° C.for 10 minutes and filtered. The filtrate was heated to 70-75° C. for 10minutes, purified water (15 vol) was added and the mixture was stirredat 60-65° C. for 30 minutes before cooling to 25-30° C. with stirringfor 30 minutes. The precipitated solid was filtered, washed withpurified water (2×5 vol) and dried at 75-80° C. under reduced pressureto afford dipyridamole as a yellow crystalline solid.

Yield (w/w and molar)=90-95%HPLC purity ≧99.9%

It will be understood that the present invention has been describedabove by way of example only. The examples are not intended to limit thescope of the invention. Various modifications and embodiments can bemade without departing from the scope and spirit of the invention, whichis defined by the following claims only.

1. Dipyridamole with a chemical purity of greater than 99%. 2.Dipyridamole according to claim 1: (i) with a chemical purity of greaterthan 99.5%; and/or (ii) with a chemical purity of greater than 99.8%;and/or (iii) with a chemical purity of greater than 99.9%; and/or (iv)comprising less than 0.1% of one or more of impurities A to G accordingto FIG. 1; and/or (v) comprising less than 0.05% of one or more ofimpurities A to G according to FIG.
 1. 3. Dipyridamole comprising lessthan 0.1% of one or more of impurities A to G according to FIG.
 1. 4.Dipyridamole according to claim 3: (i) comprising less than 0.05% of oneor more of impurities A to G according to FIG. 1; and/or (ii) with achemical purity of more than 99%; and/or (iii) with a chemical purity ofmore than 99.5%; and/or (iv) with a chemical purity of more than 99.8%;and/or (v) with a chemical purity of more than 99.9%.
 5. Apharmaceutical composition comprising dipyridamole according to claim 1and one or more pharmaceutically acceptable excipients.
 6. Apharmaceutical composition comprising dipyridamole according to claim 3and one or more pharmaceutically acceptable excipients.
 7. A method fortreating or preventing platelet aggregation or for preventingthrombosis, ischaemic stroke or transient ischaemic attacks, the methodcomprising administering to a patient in need thereof a therapeuticallyor prophylactically effective amount of dipyridamole according toclaim
 1. 8. A method for treating or preventing platelet aggregation orfor preventing thrombosis, ischaemic stroke or transient ischaemicattacks, the method comprising administering to a patient in needthereof a therapeutically or prophylactically effective amount ofdipyridamole according to claim 3.